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- PDB-8sc2: Human OCT1 bound to diltiazem in inward-open conformation -

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Basic information

Entry
Database: PDB / ID: 8sc2
TitleHuman OCT1 bound to diltiazem in inward-open conformation
ComponentsSolute carrier family 22 member 1
KeywordsTRANSPORT PROTEIN / membrane protein / MFS / drug transporter
Function / homology
Function and homology information


acetylcholine transmembrane transporter activity / secondary active organic cation transmembrane transporter activity / putrescine transmembrane transporter activity / (R)-carnitine transmembrane transporter activity / acyl carnitine transmembrane transport / pyrimidine nucleoside transmembrane transporter activity / acetylcholine transport / serotonin transport / spermidine transmembrane transporter activity / quaternary ammonium group transmembrane transporter activity ...acetylcholine transmembrane transporter activity / secondary active organic cation transmembrane transporter activity / putrescine transmembrane transporter activity / (R)-carnitine transmembrane transporter activity / acyl carnitine transmembrane transport / pyrimidine nucleoside transmembrane transporter activity / acetylcholine transport / serotonin transport / spermidine transmembrane transporter activity / quaternary ammonium group transmembrane transporter activity / quaternary ammonium group transport / epinephrine transport / thiamine transmembrane transport / purine-containing compound transmembrane transport / spermidine transport / thiamine transport / thiamine transmembrane transporter activity / organic cation transport / Organic cation transport / organic cation transmembrane transporter activity / putrescine transport / dopamine uptake / metanephric proximal tubule development / : / dopamine:sodium symporter activity / norepinephrine:sodium symporter activity / prostaglandin transport / norepinephrine transport / prostaglandin transmembrane transporter activity / Norepinephrine Neurotransmitter Release Cycle / toxin transmembrane transporter activity / neurotransmitter transmembrane transporter activity / serotonin uptake / Abacavir transmembrane transport / dopamine transport / Na+/Cl- dependent neurotransmitter transporters / monoamine transmembrane transporter activity / monoamine transport / organic anion transmembrane transporter activity / establishment or maintenance of transmembrane electrochemical gradient / xenobiotic transport across blood-brain barrier / Neurotransmitter clearance / Ciprofloxacin ADME / xenobiotic transport / neurotransmitter transport / xenobiotic transmembrane transporter activity / transport across blood-brain barrier / lateral plasma membrane / xenobiotic metabolic process / basal plasma membrane / presynapse / basolateral plasma membrane / apical plasma membrane / membrane / identical protein binding / plasma membrane
Similarity search - Function
Organic cation transport protein/SVOP / Sugar transport proteins signature 1. / Major facilitator, sugar transporter-like / Sugar (and other) transporter / Sugar transporter, conserved site / Major facilitator superfamily domain / Major facilitator superfamily (MFS) profile. / MFS transporter superfamily
Similarity search - Domain/homology
Diltiazem / Solute carrier family 22 member 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.36 Å
AuthorsZeng, Y.C. / Sobti, M. / Stewart, A.G.
Funding support Australia, 1items
OrganizationGrant numberCountry
National Health and Medical Research Council (NHMRC, Australia)APP2016308 Australia
CitationJournal: Nat Commun / Year: 2023
Title: Structural basis of promiscuous substrate transport by Organic Cation Transporter 1.
Authors: Yi C Zeng / Meghna Sobti / Ada Quinn / Nicola J Smith / Simon H J Brown / Jamie I Vandenberg / Renae M Ryan / Megan L O'Mara / Alastair G Stewart /
Abstract: Organic Cation Transporter 1 (OCT1) plays a crucial role in hepatic metabolism by mediating the uptake of a range of metabolites and drugs. Genetic variations can alter the efficacy and safety of ...Organic Cation Transporter 1 (OCT1) plays a crucial role in hepatic metabolism by mediating the uptake of a range of metabolites and drugs. Genetic variations can alter the efficacy and safety of compounds transported by OCT1, such as those used for cardiovascular, oncological, and psychological indications. Despite its importance in drug pharmacokinetics, the substrate selectivity and underlying structural mechanisms of OCT1 remain poorly understood. Here, we present cryo-EM structures of full-length human OCT1 in the inward-open conformation, both ligand-free and drug-bound, indicating the basis for its broad substrate recognition. Comparison of our structures with those of outward-open OCTs provides molecular insight into the alternating access mechanism of OCTs. We observe that hydrophobic gates stabilize the inward-facing conformation, whereas charge neutralization in the binding pocket facilitates the release of cationic substrates. These findings provide a framework for understanding the structural basis of the promiscuity of drug binding and substrate translocation in OCT1.
History
DepositionApr 4, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 18, 2023Provider: repository / Type: Initial release
Revision 1.1Oct 25, 2023Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _citation_author.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Solute carrier family 22 member 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)59,5822
Polymers59,1671
Non-polymers4151
Water0
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein Solute carrier family 22 member 1 / Organic cation transporter 1 / hOCT1


Mass: 59167.422 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SLC22A1, OCT1 / Production host: Homo sapiens (human) / References: UniProt: O15245
#2: Chemical ChemComp-C9F / Diltiazem / Diltiazem


Mass: 414.518 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H26N2O4S / Feature type: SUBJECT OF INVESTIGATION / Comment: medication, channel blocker*YM
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Human OCT1 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2000 nm / Nominal defocus min: 500 nm
Image recordingElectron dose: 88 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING ONLY
3D reconstructionResolution: 3.36 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 1345674 / Symmetry type: POINT

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